Current models of Parkinson's disease (PD) are inadequate, 6- Hydroxydopamine destroys the nigrostriatal pathway acutely and therefore bears little resemblance to the slowly progressive neurodegeneration that characterizes PD. Similarly, the MPTP model relies on acute administration of toxin although the toxin may be given repeatedly. In addition, the MPTP model is highly variable, with some animals becoming so severely ill that they require euthanasia, other animals never achieving an adequate level of parkinsonism, and some becoming ideally parkinsonian. Thus, there is a need for a reliable model that mimics the slow progression of PD. Studies in our laboratory indicate that chronic, continuous, systemic administration of the mitochondrial toxin, rotenone, selective destroys dopaminergic terminals in motor portions of striatum and leads over a period of weeks or months to retrograde degeneration of the dopaminergic cells of substantial nigra. Remarkably, systemic rotenone accurately reproduces the dopaminergic pathology of PD: dopaminergic terminals in striatum are lost while lose in nucleus accumbens are relatively spared; terminals in olfactory tubercle are completely spared; neurons in substantial nigra pars compacta degenerate while those in the adjacent ventral tegmental area survive. In the current proposal, we will: (1) use chronic intravenous infusion of rotenone to product in rats a model of slowly progressive degeneration of nigrostriatal dopaminergic neurons. Rotenone dosing and infusion duration will be optimized; (2) determine the anatomical specificity of dopaminergic neurodegeneration produced by rotenone infusion; (3) investigate potential mechanisms involved in this form of chronic neurodegeneration. Specifically, we will look for evidence of oxidative damage, indirect excitotoxicity, and determine whether cell death occurs via apoptosis or necrosis; (4) examine the behavioral consequence of this slow dopaminergic neurodegeneration; and (5) modify this model for use in primates using chemotherapy infusion pumps. Successful development of this model will allow us to (i) reliably adjust the rate and severity of dopamine depletion by adjusting infusion rate and duration; (ii) define the relevant mechanisms of neurodegeneration in an in vivo system that more accurately models the human disease; and (iii) test potential neuroprotective strategies in an in vivo model of chronic neurodegeneration that is highly relevant to PD.